This invention was made with Government support under EYO3373 awarded by the National Eye Institute and the Federal Government has limited rights therein.
This invention relates to a method and preparation for stimulating tear secretion. More particularly, it relates to the stimulation of tear secretion with topically applied agents including certain phosphodiesterase inhibitors and certain cyclic nucleotide analogues that increase intracellular cyclic nucleotide levels in lacrimal gland tissue.
There are a number of situations where it is desirable to increase the amount and/or to modify the nature of tear fluid produced by the eye. Illustrative instances include the treatment of a spectrum of dry eye disorders including, but not limited to, keratoconjunctivitis sicca, age-related dry eye, Stevens-Johnson syndrome, ocular cicatricial pemphigoid, blepharitis, neurotrophic ocular surface disease and corneal exposure. In addition, patients who wear contact lenses may have sub-optimal rates of tear production for optimal contact lens wear. Increased tear production is likely to increase eye comfort and contact lens comfort, and improve contact lens wear. These patients will therefore benefit from agents that increase tear production.
The lacrimal gland is an exocrine gland which secretes protein and, by different mechanisms, water and electrolytes. To stimulate secretion, agonists are employed which increase intracellular free calcium concentration, and/or the concentration of adenosine 3', 5'-cyclic monophosphate (cyclic AMP or cAMP). However, proteins are secreted by exocytosis, whereas electrolytes and water are secreted as the permeability of cell membranes is selectively increased to sodium, potassium and chloride. A given agonist could stimulate water and electrolyte secretion, but not protein secretion, and visa versa.
The cyclic nucleotides, cyclic AMP, and guanosine 3', 5'-cyclic monophosphate (cyclic GMP or cGMP) are known to regulate a variety of metabolic processes. Cyclic AMP has been suggested to function as a second messenger for exocytosis in the lacrimal gland. Phosphodiesterases are enzymes responsible for the destruction of cyclic AMP by catalyzing the hydrolytic reaction of cyclic AMP and water to produce adenosine 5'-monophosphate and for the destruction of cyclic GMP by catalyzing the hydrolytic reaction of cyclic GMP and water to produce guanosine 5'-monophosphate.
Various molecular forms of phosphodiesterase are distributed in tissues and cells. Agents that inhibit phosphodiestereases may produce tissue selective responses (Weishaur, R. E. et al J. of Med. Chem. 28; 537-545, 1985).
It is known that the phosphodiesterase inhibitors theophylline, 3-isobutyl-1-methylxanthine (IBMX), and pentoxfylline increase cyclic AMP levels in lacrimal gland cells and stimulate protein secretion from lacrimal gland tissue pieces or cells in vitro (Friedman Z. Y. et al, Biochemica et Biophysica Acta 675: 40-45, 1981: Jahn R. et al, Eur. J. Biochem 126: 623-629, 1982; Mauduit P. et al, Am J. Physiol J. 246; C37-C44, 1984; Dartt D. A. et al, J. Physiol (London) 352; 375-384, 1984).
Cellular cyclic nucleotide levels can also be increased by exogenous addition of cyclic nucleotide analogues to which cells are permeable. Cells are not permeable to cyclic AMP or cyclic GMP, thus the exogenous addition of these compounds does not elevate cellular cyclic nucleotide levels.
It is know that exogenous 8-bromo cyclic AMP, dibutyryl cyclic AMP or adenosine 3'-5'-cyclic phosphorothioate stimulate protein secretion from lacrimal gland tissue pieces or cells in vitro, but 8-bromo cyclic GMP does not. (Friedman Z. Y. et al, Biochemica et Biophysica Acta 675: 40-45, 1981: Jahn R. et al, Eur. J. Biochem 126: 623-629, 1982; Mauduit P. et al, Am. J. Physiol J. 246; C37-C44, 1984; Dartt D. A. et al, J. Physiol (London) 352; 375-384, 1984.)
What is needed are agents which will stimulate tear secretion upon topical administration to the ocular surface. A topical mode of administration has several advantages. It eliminates the need for injections in patents with dry eye disorders, thereby decreasing systemic effects, cost of therapy, and the amount of drug needed.
Accordingly, it is an object of this invention to provide an improved method for stimulating tear secretion by topical administration. It is another object of this invention to provide an improved method of stimulating lacrimal gland secretion by topical application of compounds to the ocular surface. It is also an object to provide an improved method for the treatment of dry eye disorders. Another object of the present invention is to facilitate the treatment of dry eye disorders without systemic therapy such as injection. A further object is to provide an improved agent for topical application to improve eye comfort. It is another object of the present invention to provide an agent for topical application to enhance contact lens wear and comfort. A further object is to provide a method for increasing the amount of the tear fluid produced by lacrimal gland tissue. Other objects of the invention will in part be obvious and will in part appear hereinafter.